Patent EA-004952-B1 (EA)
Title: Process for preparing a ketimine
Inventor: COLBERG JUAN CARLOS
IPC: C07C249/02
Filed: 1998-10-15
Abstract: 1. A process for preparing N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-napthalenylidene]methaneamine, formula II comprising reacting 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-napthalenone, formula I with monomethylamine in an alcohol solvent selected from primary, secondary and tertiary straight or branched (C1-C6) alkanols and other alcohols having a boiling point, under reaction conditions, that is greater than about 55 degree C, and in which monomethylamine is soluble. 2. A process for preparing N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene (sertraline), comprising hydrogenation of the ketimine product of formula II that is formed in such reaction to form a mixture of racemic cis-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene and racemic trans-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene. 3. A process for preparing the optically pure (+) enantiomer of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-napthalenylidene]methaneamine, formula II' or an optionally enriched (+) mixture of the (+) and (-) enantiomers of the same, respectively comprising reacting the optionally pure (+) enantiomer 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-napthalenone, formula I' or an optionally enriched (+) mixture of the (+) and (-) enantiomers of the same, respectively, with monomethylamine in a solvent selected from primary, secondary and tertiary straight or branched (C1-C6) alkanols and other alcools having a boiling point, under reaction conditions, that is greater than about 55 degree C, and in which monomethylamine is soluble. 4. A process for preparing N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene, wherein the optically pure or optically enriched (+) ketimine product of formula II' or an optically enriched (+) mixture of the (+) and (-) enantiomers of the same, that is formed in such reaction is hydrogenated to form an optically pure (+) mixture of cis (+)-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene and trans (+) N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene or optically enriched (+) mixture of cis (+)-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene and trans-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene, cis (-)-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene and trans (-)-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene. 5. A process according to claim 1 wherein an excess of monomethylamine with respect to the napthalenone -1 of formula I is employed. 6. A process according to claim 1 wherein the reaction is conducted at a temperature in the range of about 50 degree C to about 120 degree C and a pressure in the range of about atmospheric pressure to about 100 psig (680 kPa). 7. A process according to claim 1 wherein the solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, phenol, and benzylalcohol. 8. A process according to claim 1 wherein the solvent is methanol. 9. A process according to claim 1 wherein the solvent is isopropanol. 10. A process according to claim 1 wherein the solvent is n-propanol. 11. A process according to claim 1 wherein the solvent is ethanol. 12. A process according to claim 2 wherein the ketimine product of formula II is hydrogenated in situ in the same alcohol in which it was formed to yield a mixture of racemic cis-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene and racemic trans-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene. 13. A process according to claim 3 wherein an excess of monomethylamine with respect to the optically active napthalenone-1 of formula I is employed. 14. A process according to claim 3 wherein the reaction is conducted at a temperature in the range of about 50 degree C to about 120 degree C and a pressure in the range of about atmospheric pressure to about 100 psig (680 kPa). 15. A process according to claim 3 wherein the solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, phenol, and benzylalcohol. 16. A process according to claim 3 wherein the solvent is methanol. 17. A process according to claim 3 wherein the solvent is isopropanol. 18. A process according to claim 3 wherein the solvent is n-propanol. 19. A process according to claim 3 wherein the solvent is ethanol. 20. A process according to claim 4 wherein the ketimine product of formula II' is hydrogenated in situ in the same alcohol in which it was formed to yield an optically pure mixture of cis (+)-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene and trans (+) N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene or of cis (+)-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene and trans-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene, cis (-)-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene and trans (-)-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene. 21. A process for preparing a mixture of racemic cis-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene and trans (+) N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene, comprising reacting a compound of the formula I' with monomethylamine, hydrogen gas, and a hydrogenation catalyst in a solvent selected from primary, secondary and tertiary straight or branched (C1-C6) alkanols, and other alcohols having a boiling point, under reaction conditions, that is greater than about 55 degree C and in which monomethylamine is soluble. 22. A process for preparing the optically pure (+) mixture of cis (+)-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene and trans (+)-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene or optically enriched (+) mixture of cis (+)-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene and trans-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene, cis (-)-N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene and trans (-) N-methyl-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenylidene, comprising reacting a compound of the formula I' with monomethylamine, hydrogen gas, and a hydrogenation catalyst in a solvent selected from primary, secondary and tertiary straight or branched (C1-C6) alkanols, and other alcohols having a boiling point, under reaction conditions, that is greater than about 55 degree C and in which monomethylamine is soluble.